Pemafibrate reduced very low density lipoprotein (VLDL) cholesterol, triglycerides, remnant cholesterol, and apolipoprotein C-III levels but do not lower the incidence of cardiovascular events among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol levels, and low LDL cholesterol levels, according to study findings published in The New England Journal of Medicine.
Researchers tested the hypothesis that patients with concomitant type 2 diabetes, high triglyceride levels, and low HDL cholesterol levels might benefit clinically from decreased triglyceride levels. The primary outcome was the first occurrence of a major adverse cardiovascular event, defined as a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes.
The researchers conducted the double-blind, randomized, placebo-controlled PROMINENT (Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes; ClinicalTrials.gov Identifier: NCT03071692) trial, a multinational event (24 countries) conducted from March 2017 to September 2020, sponsored by Kowa Research Institute, a subsidiary of Kowa, the developer and marketer of pemafibrate. The analysis was performed by the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital, Boston, Massachusetts.
The trial included 10,497 patients (66.9% with previous cardiovascular disease) with type 2 diabetes, HDL cholesterol levels of 40 mg/dL or lower, and mild-to-moderate hypertriglyceridemia (triglyceride level, 200-499mg/dL). The patients were randomly assigned to either pemafibrate treatment (0.2 mg tablets twice daily; n=5240) or a matching placebo (n=5257). Baseline characteristics were balanced between the groups and representative of patients with type 2 diabetes and mixed dyslipidemia (median age, 64 years; 27.5% women; 19.4% Hispanic/Latinx).
Participants included men who were at least 50 years of age and women at least 55 years of age who had not had atherosclerotic cardiovascular disease, or anyone at least 18 years of age with atherosclerotic cardiovascular disease. Eligibility also included patients receiving a stable dose of a qualifying moderate- or high-intensity statin, who were untreated, or were receiving other lipid-lowering therapy and had a documented LDL concentration of 70 mg/dL or less in the previous 12 months.
Overall, at baseline 95.7% were receiving statin therapy and 80.1% were receiving an angiotensin-converting enzyme inhibitor or an angiotensin II-receptor blocker.
Those with type 1 diabetes, uncontrolled diabetes, severe heart failure or kidney disease, untreated hypothyroidism or hyperthyroidism, or a clinically significant liver disease were excluded.
The baseline median fasting levels were triglyceride (271 mg/dL), LDL cholesterol (78 mg/dL), and HDL cholesterol (33 mg/dL). Median follow-up was 3.4 years. Trial disruptions occurred with medication delivery due to the COVID-19 pandemic and conflict in the Ukraine. Researchers noted a mean adherence of 81.6% at the end of the trial.
Researchers found the effects of pemafibrate vs placebo at 4 months (triglycerides
-26.2%; VLDL cholesterol -25.8%; remnant cholesterol [cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling] -25.6%; apolipoprotein C-III -27.6%; apolipoprotein B +4.8%).
They noted a primary outcome event in the pemafibrate group (572 patients) and in the placebo group (560 patients) (hazard ratio, 1.03; 95% CI, 0.91-1.15) with no noticeable effect modification in any prespecified group.
There was no significant difference between groups in incidence of serious adverse events, however pemafibrate associated with higher incidence of venous thromboembolism and renal events and a lower incidence of nonalcoholic fatty liver disease.
“In this randomized, placebo-controlled trial involving patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, low levels of HDL cholesterol, and well-controlled levels of LDL cholesterol, pemafibrate did not reduce the risk of cardiovascular events,” the researchers wrote. “However, this agent was associated with lower triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels.”
Disclosure: This research was supported by Kowa Research Institute. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Das Pradhan A, Glynn RJ, Fruchart JC, et al.; on behalf of the PROMINENT Investigators. Triglyceride lowering with pemafibrate to reduce cardiovascular risk. N Engl J Med. Published online November 24, 2022. doi:10.1056/NEJMoa2210645